Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• This invention relates to novel compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia.
• R 1 represents C 1-4 alkoxy optionally substituted by one or more fluorine atoms
• R 2 represents an aryl group or a heteroaryl group, optionally substituted by C 1-4 alkyl or SO 2 NH 2 ;
• R 3 represents a 4-, 5-, 6-, or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C 1-4 alkyl, C 1-4 alkoxy, halogen and NHSO 2 (C 1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms;
• X represents CH or N
• A represents CO or SO 2 ;
• Z represents CH or N
• n 1 or 2, and in addition, when Z represents CH, it may represent 0;
• n 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5;
• a and Z are as defined above;
• R 4 and R 5 independently represent H or C 1-4 alkyl
• p 1, 2 or 3, and in addition, when Z represents CH, it may represent 0;
• Pharmaceutically acceptable salts include acid addition salts, such as hydrochloride and hydrobromide salts, and phosphate salts.
• Alkyl or alkoxy groups that R 1-5 may represent or include can be straight chain, branched chain, cyclic, or a combination thereof.
• Aryl in the definition of R 2 means an aromatic hydrocarbon, for example phenyl or naphthyl.
• Heteroaryl in the definition of R 2 means an aromatic heterocycle, for example one having 5 or 6 ring members, at least one of which is N, O or S, such as pyridinyl or furanyl.
• heterocyclic rings represented or comprised by R 3 are saturated.
• examples include morpholine, thiomorpholine-1,1-dioxide, 1,4-dioxan, tetrahydrofuran and piperidine.
• the compounds of the invention may be optically active.
• the invention includes all optical isomers of the compounds of formula I, and all diastereoisomers thereof.
• the compounds of the invention may exist in a number of tautomeric forms.
• the invention includes all such tautomeric forms.
• R 1 represents methoxy
• R 2 represents phenyl or 2-pyridinyl
• R 3 represents morpholinyl, or a piperidine ring which is fused to a benzene or pyridine ring;
• R 3 represents a piperidine ring fused to a benzene ring which is substituted by NHSO 2 (C 1-4 alkyl).
• R 3 is as defined above, A represents CO or SO 2 and Lg represents a leaving group;
• R 2 is as defined above and M represents substituted boron, zinc or tin, in the presence of a palladium catalyst;
• R 3-5 , A, Z, m, n and p are as defined above; and R 3a has the same significance as R 3 above except that it contains a nucleophilic nitrogen atom in the heterocyclic ring which is attached to the H in formula VIIIc;
• R 1 , R 2 , R 4 , R 5 , X, Z, m, n and p are as defined above, and Lg is a leaving group, with a compound of formula VIIIc, as defined above; or
• the cyclization may be carried out in the presence of a strong base (for example lithium diisopropylamide) in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), around room temperature.
• a strong base for example lithium diisopropylamide
• a solvent that does not adversely affect the reaction for example tetrahydrofuran
• it may be performed using potassium hydroxide in a solvent which does not adversely affect the reaction (for example dimethylsulphoxide), at the reflux temperature of the solvent.
• suitable leaving groups are OH and Cl.
• the reaction may be carried out in the presence of conventional coupling agents [for example 1-hydroxybenzotriazole monohydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-methylmorpholine] in a solvent which does not adversely affect the reaction (for example CH 2 Cl 2 ) at or around room temperature.
• the leaving group is Cl
• the reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH 2 Cl 2 or tetrahydrofuran), around 0° C. or up to the reflux temperature of the solvent.
• suitable leaving groups include the trifluoromethylsulphonate (triflate) group.
• the palladium catalyst may be tetrakis(triphenylphosphine)palladium(0).
• M may be B(OH) 2 , B(CH 2 CH 2 ) 2 , Sn(CH 2 CH 2 CH 2 CH 3 ) 3 , Sn(CH 3 ) 3 or ZnCl.
• the reaction may be carried out in a solvent that does not adversely affect the reaction (for example, when M is B(OH) 2 , a mixture of toluene, ethanol and 1M aqueous sodium carbonate) at an elevated temperature (for example the reflux temperature of the solvent).
• the reaction may be carried out in a solvent which does not adversely affect the reaction (for example n-butanol) in the presence of a base (for example triethylamine) at an elevated temperature (for example 100° C.).
• a solvent which does not adversely affect the reaction for example n-butanol
• a base for example triethylamine
• suitable leaving groups include Cl.
• the reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF) in the presence of a base (for example triethylamine) at room temperature.
• a solvent that does not adversely affect the reaction for example THF
• a base for example triethylamine
• the reaction may also be carried out without isolating the compound of formula IXa or IXb, by reacting a compound of formula IIIa or IIIb with triphosgene and a compound of formula VIIIc.
• the leaving group is —Cl.
• the reaction may be carried out in a solvent that does not adversely affect the reaction (for example CH 2 Cl 2 ) in the presence of a base (for example triethylamine) at or around room temperature.
• suitable strong bases include lithium diisopropylamide.
• the reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF).
• R 1 , R 3 and L are as defined above and Lg is a leaving group (such as a triflate group), with a compound of formula VI, as defined above, using the conditions described for process (c) above.
• Compounds of formula X may be prepared by converting the OH group in a compound of formula XI.
• R 1 , R 3 and L are as defined above, into a leaving group (such as a triflate), for example by reaction with triflic anhydride.
• the reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH 2 Cl 2 ) in the presence of pyridine, below room temperature (for example ⁇ 20° C.).
• R 1 , R 3 and L are as defined above and Pg is a hydroxy protecting group (such as benzyl).
• Pg is a hydroxy protecting group
• the deprotection may be achieved by hydrogenation over palladium-on-charcoal, in ethanol, around room temperature.
• R 1 , R 2 , R 4 , R 5 , m, n and p are as defined above, by cyclization using potassium hydroxide or lithium diisopropylamide at an elevated temperature (such as 90° C.) in DMSO, quenching with water.
• Compounds of formula XVIIa or XVIIb may be prepared by reacting a compound of formula XIII, as defined above, with a compound of formula XVIIIa or XVIIIb, as appropriate,
• R 1 , R 3 and L are as defined above, into a leaving group (such as a triflate group), for example by reaction with triflic anhydride.
• Compounds of formula VIIIa and VIIIb may be prepared by reaction of a compound of formula IV, as defined above, with a compound of formula XIXa or XIXb, as defined above, as appropriate, using the conditions indicated for process (d) above.
• the compounds of the invention are useful because they possess pharmacological activity in animals.
• the compounds are useful in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia.
• the latter condition is of greatest interest.
• a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering from such a disorder.
• the use of the compounds of the invention as pharmaceuticals, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of benign prostatic hyperplasia are also provided.
• the compounds of the invention may be administered by any convenient route, for example orally, parenterally (e.g. intravenously, transdermally) or rectally.
• the daily dose required will of course vary with the particular compound used, the particular condition being treated and with the severity of that condition. However, in general a total daily dose of from about 0.01 to 10 mg/kg of body weight, and preferably about 0.05 to 1 mg/kg, is suitable, administered from 1 to 4 times a day.
• the compounds of the invention will generally be administered in the form of a suitable pharmaceutical formulation.
• a pharmaceutical formulation including preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the pharmaceutical formulation is preferably in unit dose form.
• Such forms include solid dosage forms, for example tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical vehicles.
• Solid formulations may be prepared by mixing the active ingredient with pharmaceutical carriers, for example conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation formulation in which the active ingredient is uniformly dispersed so that it may be readily subdivided into equally effective unit dosage forms containing typically from 0.1 to about 500 mg of the active ingredient.
• the solid dosage forms may be coated or otherwise compounded to prolong the action of the formulation.
• the formulations of the invention may also contain a human 5- ⁇ reductase inhibitory compound [see International Patent Application WO 95/28397], or a compound of the invention could be presented in a pharmaceutical pack also containing a human 5- ⁇ reductase inhibitory compound as a combined preparation for simultaneous, separate or sequential use.
• the compounds of the invention may be tested in the screens set out below.
• Prostatic tissue was cut into longitudinal strips (approximately 3 ⁇ 2 ⁇ 10 mm) and suspended in organ baths under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCl (119), KCl (4.7). CaCl 2 (2.5), KH 2 PO 4 (1.2), MgSO 4 (1.2), NaHCO 3 (25), glucose (11), and gassed with 95% O 2 /5% CO 2 .
• the solution also contained 10 mM cocaine and 10 mM corticosterone. Tissues were exposed to a sensitising dose of ( ⁇ )-noradrenaline (100 mM) and washed over a 45 minute period.
• Mature male beagles (12-15 kg body weight) were anaesthetised with sodium pentobarbitone (30-50 mg/kg i.v.) and a tracheal cannula was inserted. Subsequent anaesthesia was maintained using pentobarbitone infusion.
• the animals were respirated with air using a Bird Mk8 respirator (Bird Corp., Palm Springs, Calif. USA) adjusted to maintain blood gasses in the range pO 2 90-110 mm Hg, pCO 2 35-45 mm Hg, pH 7.35-7.45. Body temperature was maintained at 36-37.5° C. using a heated operating table. Catheters were placed into the left femoral artery for recording blood pressure and into the left femoral vein for compound administration.
• Heart rate was recorded via the lead II E.C.G.
• a laparotomy was performed to cannulate both ureters to prevent chance of fluid volume within the bladder.
• a 7F cardiac catheter (with a 1.5 ml capacity balloon tip) was inserted into the bladder via the urethra. The balloon was filled with air and the catheter withdrawn until the balloon became lodged in the prostate, which was confirmed by digital pressure. Balloon pressure was recorded via a Druck transducer. Prostatic pressure and haemodynamic parameters were made on a Grass Polygraph (Grass Instruments. Quincy, Mass, U.S.A.) and the data measured on line using a Motorola 68000-based microcomputer system (Motorola Inc., Temple, Ariz., U.S.A.).
• Compounds were made up in PEG 300 and administered i.v. through a catheter in the femoral vein. Responses to phenylephrine (1-16 ⁇ g/kg i.v. in saline) were obtained to generate control dose-response curves (two control curves for each experiment). Compounds were administered (in terms of compound base) at 10-300 ⁇ g/kg i.v. 5 min before construction of phenylephrine curves (constructed up to a maximum dose of 128 ⁇ g/kg in the presence of test compound).
• the compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective (in particular they may have beneficial effects in benign prostatic hyperplasia without causing undesirable cardiovascular effects, for example because they are able to selectively antagonise prostatic receptor subtypes of the ⁇ 1 -adrenoceptor), or have other more useful properties than the compounds of the prior art.
• the subtitle compound was prepared by the method of Intermediate 1(b) from the compound of Intermediate 1(a) and 4-morpholinesulphonyl chloride [Repine et al, J. Med. Chem., 34, 1935 (1991)].
• the reaction mixture was partitioned between CH 2 Cl 2 and 1N NaOH.
• the organic phase was washed with 1N HCl, then H 2 O and dried over MgSO 4 and evaporated under reduced pressure.
• step (a) A solution of the product of step (a) (3.50 g, 15.7 mmol) in EtOH (250 ml) was treated with platinum dioxide (1.5 g) and 1N HCl (15.7 ml). The mixture was hydrogenated at a pressure of 414 kPa (60 psi) for 16 h, after which time the reaction mixture was filtered. The filtrate was evaporated under reduced pressure and triturated with CH 2 Cl 2 to afford the subtitle compound as a colourless solid. The solid residue from the filtration was taken up into MeOH/H 2 O (1:2 v/v), and the suspension filtered, washing with CH 2 Cl 2 (3 ⁇ ). This filtrate was evaporated to afford a second crop of the subtitle compound (total yield 3.45 g, 84%).
• step (b) To a solution of the product of step (b) (2.87 g, 10.9 mmol) in CH 2 Cl 2 at 0° C. was added acetic anhydride (1.2 ml, 13.1 mmol) and triethylamine (3.4 ml, 24.0 mmol), and the reaction was stirred at room temperature for 16 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution and the aqueous phase extracted with further portions of EtOAc. The combined organic extracts were dried over MgSO 4 and evaporated to afford an oil.
• acetic anhydride 1.2 ml, 13.1 mmol
• triethylamine 3.4 ml, 24.0 mmol
• step (a) To a solution of the product of step (a) (30.0 g, 0.13 mol) in CH 2 Cl 2 (1.31) was added pyridine (32.0 ml, 0.40 mol) and the mixture stirred at room temperature for 66 h, after which time it was cooled to ⁇ 20° C. and triflic anhydride (32.5 ml, 0.20 mol) was added dropwise. The reaction mixture was allowed to warm to room temperature over 3 h and then stirred for a further 3 h. After this, H 2 O (500 ml) was added, the organic layer was separated, dried over MgSO 4 and evaporated under reduced pressure to afford a yellow oil.
• step (b) A solution of the product of step (b) (15.0 g, 40 mmol) in toluene (200 ml) and EtOH (100 ml) was treated with phenylboronic acid (6.1 g, 50 mmol), tetrakis(triphenylphosphine)palladium (2.4 g, 2 mmol) and 2N aqueous sodium carbonate (45 ml) and the mixture was heated to reflux for 1 h. The mixture was then cooled and partitioned between EtOAc and H 2 O.
• phenylboronic acid 6.1 g, 50 mmol
• tetrakis(triphenylphosphine)palladium 2.4 g, 2 mmol
• 2N aqueous sodium carbonate 45 ml
• step (c) To a solution of the product of step (c) (12.19 g, 43 mmol) in CH 2 Cl 2 (200 ml) was added tetra-n-butylammonium chloride (7.1 g, 26 mmol) followed by a suspension of sodium dithionite monohydrate (81.6 g, 430 mmol) in H 2 O (250 ml) and the resulting mixture was stirred rapidly for 30 min at room temperature. A further portion of sodium dithionite monohydrate (40.8 g, 215 mmol) in H 2 O (150 ml) was added and stirring continued for a further 30 min at room temperature.
• step (d) To a solution of the product of step (d) (10.75 g, 41.8 mmol) in CH 2 Cl 2 (200 ml) was added sodium cyanate (10.88 g, 167 mmol) followed by trifluoroacetic acid (13.3 ml, 167 mmol) and the reaction was stirred for 18 h at room temperature. The mixture was then partitioned between CH 2 Cl 2 and H 2 O, the organic layer was separated, dried over MgSO 4 and evaporated under reduced pressure to afford a yellow solid. This was suspended in aqueous NaOH (16.7 g in 150 ml H 2 O) and warmed to 70° C.
• step (e) (10.15 g, 40 mmol) was combined with phosphorus oxychloride (52.8 ml, 570 mmol) and N,N-dimethylaniline (12.0 ml, 90 mmol) and the mixture was heated to reflux for 1.5 h. The reaction mixture was then evaporated under reduced pressure, azeotroping with toluene (2 ⁇ ), and the resulting solid was partitioned between EtOAc and H 2 O. The organic layer was separated and dried over MgSO 4 , then passed through a plug of silica gel, washing with EtOAc, and evaporated to afford a yellow solid.
• step (f) To a solution of the product of step (f) (300 mg, 1.05 mmol) and Intermediate 3 (300 mg, 1.05 mmol) in n-BuOH (5 ml) was added triethylamine (0.31 ml, 2.2 mmol), and the mixture was heated at 100° C. for 18 h. After cooling, the reaction mixture was evaporated under reduced pressure, partitioned between CH 2 Cl 2 and saturated aqueous NaHCO 3 . The organic layer was separated and dried over MgSO 4 to afford a brown solid. Trituration in hot isopropanol afforded the title compound as a colourless solid (86 mg, 16%). R f 0.22 (CH 2 Cl 2 /MeOH 95/5, v/v).
• step (a) A solution of the product of step (a) (170 mg. 1.0 mmol) in CH 2 Cl 2 (20 ml) at ⁇ 20° C. was treated-sequentially with N,N-diisopropylethylamine (0.23 ml, 1.32 mmol) and triphosgene (90 mg, 0.31 mmol) and the reaction mixture stirred under N 2 for 1 h at room temperature. Evaporation under reduced pressure afforded the crude subtitle compound (207 mg. quantitative) which was used without further purification. R f 0.76 (CH 2 Cl 2 /MeOH/0.88 NH 3 90/10/1, v/v).
• step (a) To a solution of the product of step (a) (250 mg, 0.77 mmol) in CH 2 Cl 2 was added (R/S)-tetrahydrofuran-2-carboxylic acid (99 mg, 0.85 mg), 1-hydroxybenzotriazole hydrate (157 mg, 1.16 mmol), 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) and triethylamine (0.16 ml, 1.16 mmol) and the reaction was stirred at room temperature under N 2 for 18 h.
• Example 4(a) The title compound was prepared by the method of Example 4(a) from the compound of Example 1(f) and N-methyl-1,3-propanediamine, followed by reaction with 4-morpholinecarbonyl chloride using the method of Intermediate 1(b). MS m/z 498 (MH + ).
• Example 4(a) The compound of Example 4(a) was reacted with 4-morpholinecarbonyl chloride using the method of Intermediate 1(b) to give the title compound. MS m/z 437 (MH ⁇ ).
• Example 1(g) The title compound was prepared by the method of Example 1(g) from the compound of Example 1(f) and 5,6,7,8-tetrahydro-1,6-naphthyridine [Shiozawa et al. Chem. Pharm. Bull., 32, 2522 (1984)]. MS m/z 384 (MH ⁇ ).
• step (a) A solution of the product of step (a) (43.8 g. 0.18 mol) in glacial acetic acid (87 ml) was added dropwise to concentrated nitric acid (70% w/w, 244 ml) with periodic cooling to maintain the reaction temperature below 30° C. Once the addition was complete, the reaction was stirred for a further 30 min, after which time the mixture was poured into H 2 O (1 l) and stirred for 30 min. The resulting precipitate was isolated by filtration, washed with H 2 O and dried under reduced pressure at 50° C. to afford the subtitle compound as a white solid (35.1 g, 68%). R f 0.70 (EtOAc/hexane 1/1, v/v).
• step (b) To a solution of the product of step (b) (35.0 g, 0.12 mol) in CH 2 Cl 2 (500 ml) was added tetra-n-butylammnonium chloride (20.3 g, 0.074 mol) followed by a solution of sodium dithionite hydrate (118.0 g, 0.61 mol) in H 2 O (400 ml) and the mixture was stirred vigorously for 2 h at room temperature. A further quantity of sodium dithionite hydrate (47.2 g) was then added and stirring continued for 1 h. The reaction mixture was then basified with 2N aqueous NaOH and the phases separated.
• step (c) A solution of the product of step (c) (26.7 g, 0.10 mol) in CH 2 Cl 2 was treated with sodium cyanate (17.1 g, 0.26 mol) and trifluoroacetic acid (20.9 ml, 0.26 mol) was added dropwise to the resulting mixture at room temperature. After 45 min, the mixture was diluted with CH 2 Cl 2 (1 l) and stirred for a further 18 h. The mixture was then concentrated under reduced pressure and partitioned between MeOH and 2N aqueous NaOH and stirred for 2 h. The MeOH was then removed under reduced pressure and the yellow solid isolated by filtration, washing sequentially with H 2 O, acetone and ether to afford the subtitle compound as a yellow solid (18.0 g, 54%).
• step (d) DMF (7.9 ml, 0.10 mol) was added dropwise to phosphorus oxychloride (47.9 ml, 0.52 mol) with stirring. After 10 min, the product of step (d) (16.4 g, 0.055 mol) was added portionwise and the resulting mixture heated at 90° C. for 1.5 h, then cooled and poured into EtOAc (750 ml). The mixture was neutralised by the portionwise addition of aqueous sodium carbonate and the phases were separated. The organic layer was evaporated to dryness and the residue combined with the organic phase that was then treated with aqueous NaOH to basify (pH 10) and the mixture was heated at 90° C. for 2 h.
• the subtitle compound was prepared by the method of Example 1(g) from the product of step (e) and Intermediate 1.
• the product was purified on silica gel eluting with EtOAc/MeOH (9/1, v/v) to afford the subtitle compound (46%) as a foam.
• R f 0.67 (CH 2 Cl 2 /MeOH/0.88 NH 3 84/14/2, v/v).
• step (f) The product of step (f) (360 mg, 0.73 mmol) was dissolved in EtOH (60 ml), 10% palladium on charcoal (100 mg, 0.09 mmol) was added and the reaction mixture hydrogenated at room temperature at a pressure of 414 kPa (60 psi) for 18 h. The reaction mixture was filtered and concentrated under reduced pressure and the residue purified on silica gel, eluting with CH 2 Cl 2 /MeOH/0.88 NH 3 (92/7/1, v/v) to afford the subtitle compound as foam (135 mg. 47%). R f 0.33 (CH 2 Cl 2 /MeOH/0.88 NH 3 84/14/2. v/v). MS m/z 403 (MH ⁇ ).
• step (g) To a solution of the product of step (g) (3.3 g, 8.2 mmol) in CH 2 Cl 2 (80 ml), pyridine (2.0 ml, 25 mmol) was added. The solution was cooled to ⁇ 20° C. and triflic anhydride (2.0 ml, 12.3 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for a further 18 h, after which time it was partitioned between CH 2 Cl, and H 2 O, the solid residue dissolved in EtOAc and the organic layers combined, washed with water, dried over MgSO 4 and evaporated under reduced pressure.
• step (h) To a solution of the product of step (h) (200 mg, 0.37 mmol) in dioxan (5 ml) was added trimethylphenylstannane (0.71 ml, 0.37 mmol), lithium chloride (48 mg, 1.11 mmol) and tetrakis(triphenylphosphine)palladium (9 mg, 0.007 mmol) and the reaction mixture heated to reflux for 18 h under N 2 . After cooling and evaporation under reduced pressure, the residue was dissolved in CH 2 Cl 2 , filtered through a pad of Hyflo® diatomaceous earth and evaporated under reduced pressure.
• the subtitle compound was prepared by the method of Example 11(g) from the product of step (a). This afforded the subtitle compound (90%) as a colourless solid. R f 0.47 (CH 2 Cl 2 /MeOH 9/1, v/v).
• the subtitle compound was prepared by the method of Example 11(h) from the product of step (b). This afforded the subtitle compound (54%).
• R f 0.70 (CH 2 Cl 2 /MeOH 9/1, v/v)
• the subtitle compound was prepared by the method of Example 14 from the product of step (c) using phenylboronic acid. This afforded the subtitle compound as a colourless solid (75%). R f 0.34 (CH 2 Cl 2 /MeOH 95/5, v/v). MS m/z 461 (MH + ).
• step (e) To a solution of the product of step (e) (315 mg, 0.68 mmol) in THF (10 ml) at ⁇ 20° C. was added a solution of lithium diisopropylamide in THF (0.68M, 2 ml, 1.36 mmol) and the reaction allowed to warm to room temperature. The reaction mixture was poured into cooled 1N citric acid, the solution basified with Na 2 CO 3 and extracted with EtOAc.
• the subtitle compound was prepared by the method of Example 11(i) from the compound of Example 18(c) and (2-pyridinyl)tri-n-butylstannane.
• the subtitle compound was prepared from the compound of Example 1(b) by the method of Example 11(i) using (2-pyridinyl)tri-n-butylstannane.
• the product was purified by chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH (99:1) followed by trituration with ether to afford the subtitle compound (39%) as a colourless solid.
• R f 0.64 CH 2 Cl 2 /MeOH/95/5, v/v).
• step (a) To a suspension of the product of step (a) (3.30 g, 11.5 mmol) in MeOH (100 ml) was added 2N aqueous NaOH (6.3 ml, 12.6 mmol) and the reaction mixture was stirred for 64 h at room temperature followed by heating to reflux for 6 h. After cooling, the reaction mixture was concentrated under reduced pressure, the residue suspended in CH 2 Cl 2 (100 ml) and DMF (0.5 ml) was added. Oxalyl chloride (3.06 ml, 34.4 mmol) was then added and the mixture was stirred rapidly at room temperature for 4 h then evaporated under reduced pressure. The residue was suspended in CH 2 Cl 2 and poured into a rapidly stirred solution of 0.88 aqueous NH 3 .
• step (b) A solution of the product of step (b) (2.40 g, 8.8 mmol) in CH 2 Cl 2 was treated with trifluoroacetic anhydride (20 ml) and the reaction mixture stirred for 2 h at room temperature and at reflux for a further 1 h. After cooling, the reaction mixture was evaporated under reduced pressure, the residue basified with 1N aqueous NaOH and extracted with CH 2 Cl 2 (3 ⁇ ). The combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with EtOAc to afford the subtitle compound (1.73 g, 77%). R f 0.58 (EtOAc). MS m/z 256 (MH + ).
• the subtitle compound was prepared by the method of Example 1(d) from the product of step (c). The product was purified by chromatography on silica gel, eluting with EtOAc to afford the subtitle compound (69%) as a yellow solid. R f 0.46 (EtOAc). MS m/z 226 (M + ).
• the subtitle compound was prepared by the method of Example 18(a) from the product of step (d) and Intermediate 4.
• the product was purified by chromatography on silica gel, eluting with EtOAc, followed by trituration with ether to afford the subtitle compound (61%) as a pale yellow solid.
• step (e) To a solution of the product of step (e) (961 mg, 2.0 mmol) in DMSO (12 ml) was added KOH (226 mg, 4.0 mmol) and the mixture was heated to 95° C. under N 2 for 20 min. After cooling, the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed sequentially with H 2 O and saturated brine then dried over MgSO 4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH/0.88 NH 3 (92/7/1, v/v) followed by trituration with ether to afford the title compound as a colourless solid (656 mg, 69%).
• Example 11 The compound of Example 11 was tested in the first screen described above (“Contractile responses of human prostate”) and found to have a pA 2 value of 8.7.

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